Amphiphilic substances, i.e. substances with both hydrophilic and hydrophobic (lipophilic) groups, spontaneously tend to self-associate in aqueous systems forming various types of aggregates. A typical example is shown in FIG. 1 in "Cubic Mesomorphic Phases" (R. R. Balmbra, J. S. Clunie and J. F. Goodman, Nature, 222, 1159 (1969)), in which an increasing amount of amphiphile in water gives rise to micellar, cubic, hexagonal and lamellar phases. The structures of these phases are well-known, except for the cubic phases, since there are a number of cubic phases, some of which remain to be determined in detail.
Several important features of the above mentioned phases are listed below:
a) All phases are thermodynamically stable and have therefore no tendency to phase separate with time (unless chemical decomposition occurs), and they will also form spontaneously. PA1 b) All phases are characterized by having distinct hydrophilic and hydrophobic domains, which give them the possibility to dissolve (solubilize) or disperse both water-soluble and water-insoluble compounds. PA1 c) In general the rheology of the phases varies from low viscous Newtonian (dilute or moderately concentrated micellar phases) over viscous liquids to visco-elastic rigid systems (cubic phases. PA1 d) The long-range order in the hexagonal, lamellar and cubic phases, as seen inter alia in X-ray low angle diffraction, in combination with liquid-like properties on a molecular level, have given rise to the notation "liquid crystalline phases". The anisotropic phases, i.e. mainly the hexagonal and the lamellar phases, are birefringent and are therefore easily identified in the polarizing microscope. PA1 e) If oil, in a broad sense, is added to an amphiphile-water system, and the oil/water ratio is high (&gt;&gt;1), then aggregates of the reversed type may form, i.e. reversed micellar and reversed hexagonal, or alternatively, cubic structures can be obtained. These structures will also give rise to thermodynamically stable phases. PA1 f) The occurrence of the above described phases is not restricted to specific amphiphiles, but they are encountered in almost every amphiphile-oil-water system. One or two phases may be absent, and the location of the phases vary in the phase diagram, but it is not unjustified to state that the similarities are more pronounced than the differences. PA1 forming a mixture of one or more amphiphilic substances in amounts necessary to form a cubic liquid crystalline phase when placed in contact with at least one liquid selected from the group including water, glycerol, ethylene glycol and propylene glycol, adding the biologically active material to said mixture.
Several of the characteristics listed above make some of the phases formed in systems with amphiphilic substances interesting candidates for being used as matrices or barriers in controlled-release preparations. Perhaps the most important feature is the possibility to dissolve both water-soluble and water-insoluble compounds in the phases due to their amphiphilic character. Moreover, the highly ordered structures with distinct hydrophilic and hydrophobic domains put restrictions on the diffusion of added compounds, a fact which may be advantageously used for controlled-release purposes. Especially the cubic liquid crystalline phases offer many possibilities in this context due to their rheological properties, which make them useful both as tablets and pastes.
The cubic liquid crystalline phase may crudely be characterized as being either of the water-discontinuous or oil-discontinuous droplet type, or of the bi-continuous type. The droplet structures may thus be either of a "water-soluble" or of a "water-insoluble" type. Bi-continuous structures of cubic phase have been determined by V. Luzatti et al. (Nature, 215, 701 (1967)) and K. Larsson et al. (Chem. Phys. Lipids, 27, 321 (1980)). All the different forms of cubic phases can be used in controlled-release preparations which the following discussion will explain.
The cubic liquid crystalline phase can also be described as erodible or non-erodible depending on its behaviour in excess water. Furthermore, the rate of erosion depends on, besides temperature and agitation, the appearance of the phase diagram for the actual amphiphile. This dependence is extremely strong and the rate of erosion may vary by several orders of magnitude. The following three examples will illustrate the erodible and non-erodible types of cubic phases at a temperature of 37.degree. C.
In FIG. 11 in "Phase Behaviour of Polyoxyethylene Surfactants with Water" (D. J. Mitchell, G. J. T. Tiddy, L. Waring, T. Bostock and M. P. McDonald, J. Chem. Soc. Faraday Trans. 1, 79, 975 (1983)) two cubic phases are found, one at low and the other at high amphiphile concentration. The cubic phase at low concentration is built up by closed-packed micelles and this phase will erode fast in water giving a micellar solution. For the cubic phase at high concentration of amphiphile, however, the rate of erosion is much slower since it, in excess water, first is converted to a hexagonal phase, then to the other type of cubic phase which finally forms a micellar phase.
For the second case, FIG. 2 in "Optically Positive, Isotropic and Negative Lamellar Liquid Crystalline Solutions" (J. Rogers and P. A. Winsor, Nature, 216, 477 (1967)), the situation is in part similar to the cubic phase at high amphiphile concentration in the first example, except that now the cubic phase is converted to a lamellar phase, which then turns into a micellar solution. In this system the micelles are thermodynamically rather unstable as demonstrated by a low solubility of surfactant in aqueous solution. This will have the effect of decreasing the rate of erosion.
The third example, FIG. 7 (monoolein-water) in "Food Emulsifiers and Their Associations with Water" (N. Krog and J. B. Lauridsen, in "Food Emulsions" (ed. S. Friberg), Marcel Dekker Inc. (1976)), shows a cubic phase which will, when in water, be in equilibrium with a monomer solution of amphiphile in water (10.sup.-6 M). This cubic phase will stay unchanged in excess water (at least for extremely long times).
The choice of an erodible or a non-erodible cubic phase in a controlled-release preparation depends on the required rate profile, the solubility of the compound, which rate one wants to control etc. For example, if the active substance is an almost water-insoluble drug, an eroding cubic phase may act as a source for molecularly dissolved drug. Of course, the use of erodible cubic phases is not limited to water-insoluble compounds, but may also be used if a relatively fast release profile is desired, or if an initial protection of a pharmaceutical compound (which may be subject to chemical degradation in contact with the high acidity of the gastric juice) is required.
Non-eroding cubic phases, stable in water, may be used for applications where longer release times are desirable. Both water-soluble and water-insoluble compounds can be used in this kind of cubic phase. The release rate of a bioactive substance from a non-erodible cubic phase may either be determined by the outer surface of the cubic phase towards the surrounding aqueous medium or the interfaces between hydrophilic and hydrophobic domain within the cubic phase, depending on whether the cubic phase is mono- or bi-continuous and the nature (hydrophilic, hydrophobic or amphiphilic) of the bioactive compound.
Fine adjustments of the release rate in any kind of cubic phase can be made by the addition of salt, glycerol, ethylene glycol, propylene glycol or any similar amphiphile of low molecular weight.
Other techniques of employing amphiphilic molecules to encapsulate biologically active materials for controlled-release purposes are described in U.S. Pat. Nos. 4,016,100; 4,145,410; 4,235,871 and 4,241,046. In these applications aggregates of other structures are involved and, furthermore, they have all in common that the amphiphile-water preparations of these methods are thermodynamically unstable (dispersions, emulsions and vesicles) and consist of at least two phases. The present invention is therefore fundamentally different from these, since the controlled-release matrices or barriers prepared by our technique will be thermodynamically stable one phase compositions. Because of the regular structure, with exact crystallographic lattices, the present invention provides a highly reproducible controlled-release system contrary to solutions involving polymers.